Spinal Muscular Atrophy (SMA), a common autosomal recessive motor neuron disorder, is the leading genetic cause of infant mortality. SMA results from the loss of the survival motor neuron gene (SMN1). SMN2, a nearly identical copy gene, is present in all SMA patients but differs by a critical nucleotide that alters exon 7 splicing efficiency. This results in low SMN levels which are not enough to sustain motor neurons. Thus, SMA is not a true loss-of-function disease, but rather one of dosage in which clinical presentation results in severe (Type I), intermediate (Type II) and mild (Type III) forms. Currently, there is no therapy for SMA but multiple points of intervention have been identified and the best pre-clinical target to date has been SMN2. An oral clinical lead drug, D157495, has been developed that increases SMN both in vitro and in vivo and enhances survival in two different mouse models of SMA. The goals of this project are to further test this lead compound in a mouse model of SMA to obtain pharmacokinetic and pharmacodynamic information (Aims 1 and 2) along with the minimal effective dose for efficacy (Aim 3) to support the filing for a new investigational drug (IND) for the treatment of SMA. The GLP toxicology studies and Chemistry Manufacturing and Control data for an IND are concurrently being collected and financially supported by Families of the SMA, the advocacy group that owns the Intellectual property for these compounds. The GLP safety package is well underway and will be complete by July of 2009. PUBLIC HEALTH RELEVANCE: We are performing pre-clinical experiments to further evaluate a clinical lead compound that increases SMN levels as well as survival and function in two different mouse models of SMA. The work proposed here will be important for helping to determine the dose, frequency and brain levels of drug required for treatment of humans with SMA. This data would help support an Investigational New Drug application to the FDA to move this compound to human clinical trials for SMA.